Pub Date : 2024-08-16DOI: 10.1007/s00401-024-02783-1
Luca Lucchino, Fabiana Mallone, Magda Gharbiya, Ludovico Alisi
{"title":"Key features of choroidal abnormalities in neurofibromatosis type 1, a commentary on “Histologic correlates of “choroidal abnormalities” in neurofibromatosis type 1 (NF1)”","authors":"Luca Lucchino, Fabiana Mallone, Magda Gharbiya, Ludovico Alisi","doi":"10.1007/s00401-024-02783-1","DOIUrl":"10.1007/s00401-024-02783-1","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02783-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1007/s00401-024-02786-y
Md Rejaul Hoq, Anllely Fernandez, Frank S. Vago, Grace I. Hallinan, Sakshibeedu R. Bharath, Daoyi Li, Kadir A. Ozcan, Holly J. Garringer, Wen Jiang, Ruben Vidal, Bernardino Ghetti
Cotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (PSEN1) gene. CWPs are round, eosinophilic amyloid-β (Aβ) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aβ peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aβ and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the PSEN1 V261I and A431E mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aβ filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aβ filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aβ filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD.
棉絮斑(CWPs)被描述为显性遗传性阿尔茨海默病(DIAD)神经病理学表型的特征,该病是由 Presenilin 1(PSEN1)基因的某些错义和缺失突变引起的。CWPs是缺乏淀粉样核心的圆形嗜酸性淀粉样-β(Aβ)斑块,在硫黄素S(ThS)制剂中可被识别,但无荧光。氨基酸末端截短和翻译后修饰的 Aβ 肽是 CWPs 的主要成分。CWPs 中可能存在 Tau 免疫阳性神经元。此外,神经纤维缠结也与 CWPs 共存。在此,我们报告了从因 PSEN1 V261I 和 A431E 突变导致的 DIAD 患者脑组织中分离出的 Aβ 和 tau 纤维的结构,这些患者具有 CWP 神经病理学表型。CWPs主要由I型Aβ丝组成,并以Ic型和Id型两种新的排列方式存在;此外,CWPs还含有I型和Ib型Aβ丝。Tau丝具有AD折叠,这在散发性AD和DIAD中已有报道。Ic 型和 Id 型 Aβ 细丝的形成可能是 CWPs 表型的基础。我们的数据与 PET 成像方法的发展相关,以最好地检测 DIAD 中的 CWPs。
{"title":"Cryo-EM structures of cotton wool plaques’ amyloid β and of tau filaments in dominantly inherited Alzheimer disease","authors":"Md Rejaul Hoq, Anllely Fernandez, Frank S. Vago, Grace I. Hallinan, Sakshibeedu R. Bharath, Daoyi Li, Kadir A. Ozcan, Holly J. Garringer, Wen Jiang, Ruben Vidal, Bernardino Ghetti","doi":"10.1007/s00401-024-02786-y","DOIUrl":"10.1007/s00401-024-02786-y","url":null,"abstract":"<div><p>Cotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (<i>PSEN1</i>) gene. CWPs are round, eosinophilic amyloid-β (Aβ) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aβ peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aβ and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the <i>PSEN1 V261I</i> and <i>A431E</i> mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aβ filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aβ filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aβ filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11327195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-14DOI: 10.1007/s00401-024-02781-3
Rehana K. Leak, Rachel N. Clark, Muslim Abbas, Fei Xu, Jeffrey L. Brodsky, Jun Chen, Xiaoming Hu, Kelvin C. Luk
Lewy body disorders are heterogeneous neurological conditions defined by intracellular inclusions composed of misshapen α-synuclein protein aggregates. Although α-synuclein aggregates are only one component of inclusions and not strictly coupled to neurodegeneration, evidence suggests they seed the propagation of Lewy pathology within and across cells. Genetic mutations, genomic multiplications, and sequence polymorphisms of the gene encoding α-synuclein are also causally linked to Lewy body disease. In nonfamilial cases of Lewy body disease, the disease trigger remains unidentified but may range from industrial/agricultural toxicants and natural sources of poisons to microbial pathogens. Perhaps due to these peripheral exposures, Lewy inclusions appear at early disease stages in brain regions connected with cranial nerves I and X, which interface with inhaled and ingested environmental elements in the nasal or gastrointestinal cavities. Irrespective of its identity, a stealthy disease trigger most likely shifts soluble α-synuclein (directly or indirectly) into insoluble, cross-β-sheet aggregates. Indeed, β-sheet-rich self-replicating α-synuclein multimers reside in patient plasma, cerebrospinal fluid, and other tissues, and can be subjected to α-synuclein seed amplification assays. Thus, clinicians should be able to capitalize on α-synuclein seed amplification assays to stratify patients into potential responders versus non-responders in future clinical trials of α-synuclein targeted therapies. Here, we briefly review the current understanding of α-synuclein in Lewy body disease and speculate on pathophysiological processes underlying the potential transmission of α-synucleinopathy across the neuraxis.
路易体疾病是一种由畸形的α-突触核蛋白聚集体构成的细胞内包涵体所定义的神经系统疾病。虽然α-突触核蛋白聚集体只是内含物的一个组成部分,与神经变性并无严格关联,但有证据表明,它们是路易体病理学在细胞内和细胞间传播的种子。α-突触核蛋白编码基因的基因突变、基因组增殖和序列多态性也与路易体疾病有因果关系。在路易体病的非家族病例中,疾病的诱因仍未确定,但可能包括工业/农业毒物、天然毒物来源和微生物病原体。也许是由于这些外周接触,路易包涵体在疾病早期出现在与颅神经 I 和 X 相连的脑区,这些脑区与鼻腔或胃肠道中吸入和摄入的环境因素相接。无论其身份如何,隐性疾病诱因最有可能(直接或间接)将可溶的α-突触核蛋白转变为不溶的、交叉β片状聚集体。事实上,患者血浆、脑脊液和其他组织中都存在富含β片的自我复制α-突触核蛋白多聚体,并可进行α-突触核蛋白种子扩增试验。因此,在未来的α-突触核蛋白靶向疗法临床试验中,临床医生应能利用α-突触核蛋白种子扩增检测将患者分为潜在应答者和非应答者。在此,我们简要回顾了目前对路易体病中α-突触核蛋白的认识,并推测了α-突触核蛋白病可能在神经轴中传播的病理生理过程。
{"title":"Current insights and assumptions on α-synuclein in Lewy body disease","authors":"Rehana K. Leak, Rachel N. Clark, Muslim Abbas, Fei Xu, Jeffrey L. Brodsky, Jun Chen, Xiaoming Hu, Kelvin C. Luk","doi":"10.1007/s00401-024-02781-3","DOIUrl":"10.1007/s00401-024-02781-3","url":null,"abstract":"<div><p>Lewy body disorders are heterogeneous neurological conditions defined by intracellular inclusions composed of misshapen α-synuclein protein aggregates. Although α-synuclein aggregates are only one component of inclusions and not strictly coupled to neurodegeneration, evidence suggests they seed the propagation of Lewy pathology within and across cells. Genetic mutations, genomic multiplications, and sequence polymorphisms of the gene encoding α-synuclein are also causally linked to Lewy body disease. In nonfamilial cases of Lewy body disease, the disease trigger remains unidentified but may range from industrial/agricultural toxicants and natural sources of poisons to microbial pathogens. Perhaps due to these peripheral exposures, Lewy inclusions appear at early disease stages in brain regions connected with cranial nerves I and X, which interface with inhaled and ingested environmental elements in the nasal or gastrointestinal cavities. Irrespective of its identity, a stealthy disease trigger most likely shifts soluble α-synuclein (directly or indirectly) into insoluble, cross-β-sheet aggregates. Indeed, β-sheet-rich self-replicating α-synuclein multimers reside in patient plasma, cerebrospinal fluid, and other tissues, and can be subjected to α-synuclein seed amplification assays. Thus, clinicians should be able to capitalize on α-synuclein seed amplification assays to stratify patients into potential responders <i>versus</i> non-responders in future clinical trials of α-synuclein targeted therapies. Here, we briefly review the current understanding of α-synuclein in Lewy body disease and speculate on pathophysiological processes underlying the potential transmission of α-synucleinopathy across the neuraxis.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-14DOI: 10.1007/s00401-024-02785-z
Kevin Y. Zhang, Megan Parker, Carly Weber-Levine, Anita Kalluri, Ignacio Gonzalez-Gomez, Eric Raabe, Jonathan C. Dudley, Christopher Gocke, Ming-Tseh Lin, Ying Zou, Mohamed Sherief, David O. Kamson, Matthias Holdhoff, Debraj Mukherjee, Victoria Croog, Karisa C. Schreck, Jordina Rincon-Torroella, Chetan Bettegowda, Charles G. Eberhart, Tejus Bale, Calixto-Hope G. Lucas
{"title":"ASXL1 inactivation and reduced H3K27me3 across central nervous system tumors","authors":"Kevin Y. Zhang, Megan Parker, Carly Weber-Levine, Anita Kalluri, Ignacio Gonzalez-Gomez, Eric Raabe, Jonathan C. Dudley, Christopher Gocke, Ming-Tseh Lin, Ying Zou, Mohamed Sherief, David O. Kamson, Matthias Holdhoff, Debraj Mukherjee, Victoria Croog, Karisa C. Schreck, Jordina Rincon-Torroella, Chetan Bettegowda, Charles G. Eberhart, Tejus Bale, Calixto-Hope G. Lucas","doi":"10.1007/s00401-024-02785-z","DOIUrl":"10.1007/s00401-024-02785-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.1007/s00401-024-02777-z
Sybren L. N. Maas, Thomas Hielscher, Philipp Sievers, Volker Hovestadt, Abigail K. Suwala, Till Acker, Michael Weller, Matthias Preusser, Christel Herold-Mende, Wolfgang Wick, Andreas von Deimling, Natalie Berghaus, Felix Sahm
{"title":"Loss over 5% of chromosome 1p is a clinically relevant and applicable cut-off for increased risk of recurrence in meningioma","authors":"Sybren L. N. Maas, Thomas Hielscher, Philipp Sievers, Volker Hovestadt, Abigail K. Suwala, Till Acker, Michael Weller, Matthias Preusser, Christel Herold-Mende, Wolfgang Wick, Andreas von Deimling, Natalie Berghaus, Felix Sahm","doi":"10.1007/s00401-024-02777-z","DOIUrl":"10.1007/s00401-024-02777-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11310275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1007/s00401-024-02768-0
Melissa J. Alldred, Harshitha Pidikiti, Kyrillos W. Ibrahim, Sang Han Lee, Adriana Heguy, Gabriel E. Hoffman, Panos Roussos, Thomas Wisniewski, Jerzy Wegiel, Grace E. Stutzmann, Elliott J. Mufson, Stephen D. Ginsberg
We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer’s disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolated from postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified > 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.
{"title":"Analysis of microisolated frontal cortex excitatory layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with Down syndrome","authors":"Melissa J. Alldred, Harshitha Pidikiti, Kyrillos W. Ibrahim, Sang Han Lee, Adriana Heguy, Gabriel E. Hoffman, Panos Roussos, Thomas Wisniewski, Jerzy Wegiel, Grace E. Stutzmann, Elliott J. Mufson, Stephen D. Ginsberg","doi":"10.1007/s00401-024-02768-0","DOIUrl":"10.1007/s00401-024-02768-0","url":null,"abstract":"<div><p>We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer’s disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolated from postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified > 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02768-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1007/s00401-024-02775-1
Nur Jury-Garfe, Javier Redding-Ochoa, Yanwen You, Pablo Martínez, Hande Karahan, Enrique Chimal-Juárez, Travis S. Johnson, Jie Zhang, Susan Resnick, Jungsu Kim, Juan C. Troncoso, Cristian A. Lasagna-Reeves
Asymptomatic Alzheimer’s disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology (i.e., beta-amyloid (Aβ) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.
{"title":"Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease","authors":"Nur Jury-Garfe, Javier Redding-Ochoa, Yanwen You, Pablo Martínez, Hande Karahan, Enrique Chimal-Juárez, Travis S. Johnson, Jie Zhang, Susan Resnick, Jungsu Kim, Juan C. Troncoso, Cristian A. Lasagna-Reeves","doi":"10.1007/s00401-024-02775-1","DOIUrl":"10.1007/s00401-024-02775-1","url":null,"abstract":"<div><p>Asymptomatic Alzheimer’s disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology (i.e., beta-amyloid (Aβ) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1007/s00401-024-02772-4
Sylwia Libard, Fredrik Tamsen, Irina Alafuzoff
It has been suggested that alcohol consumption protects against Parkinson's disease (PD). Here we assessed postmortem tissue samples from the brains and livers of 100 subjects with ages at death ranging from 51 to 93. Twenty percent of these subjects were demented. We used standardized assessment strategies to assess both the brain and liver pathologies (LP). Our cohort included subjects with none, mild, moderate, and severe LP caused by alcohol consumption. We noted a significant negative correlation of categorical data between liver steatosis and α-synuclein (αS) in the brain and a significant negative correlation between the extent of liver steatosis and fibrosis and the extent of αS in the brain. There was a significant negative association between the observation of Alzheimer’s type II astrocytes and αS pathology in the brain. No association was noted between LP and hyperphosphorylated τ (HPτ). No significant correlation could be seen between the extent of LP and the extent of HPτ, amyloid β protein (Aβ) or transactive DNA binding protein 43 (TDP43) in the brain. There were significant correlations observed between the extent of HPτ, Aβ, αS, and TDP43 in the brain and between liver steatosis, inflammation, and fibrosis. Subjects with severe LP displayed a higher frequency of Alzheimer’s type II astrocytes compared to those with no, or mild, LP. The assessed protein alterations were not more prevalent or severe in subjects with Alzheimer’s type II astrocytes in the brain. In all cases, dementia was attributed to a combination of altered proteins, i.e., mixed dementia and dementia was observed in 30% of those with mild LP when compared with 13% of those with severe LP. In summary, our results are in line with the outcome obtained by the two recent meta-analyses suggesting that subjects with a history of alcohol consumption seldom develop an α-synucleinopathy.
{"title":"Alcohol consumers with liver pathology rarely display α-synuclein pathology","authors":"Sylwia Libard, Fredrik Tamsen, Irina Alafuzoff","doi":"10.1007/s00401-024-02772-4","DOIUrl":"10.1007/s00401-024-02772-4","url":null,"abstract":"<div><p>It has been suggested that alcohol consumption protects against Parkinson's disease (PD). Here we assessed postmortem tissue samples from the brains and livers of 100 subjects with ages at death ranging from 51 to 93. Twenty percent of these subjects were demented. We used standardized assessment strategies to assess both the brain and liver pathologies (LP). Our cohort included subjects with none, mild, moderate, and severe LP caused by alcohol consumption. We noted a significant negative correlation of categorical data between liver steatosis and α-synuclein (αS) in the brain and a significant negative correlation between the extent of liver steatosis and fibrosis and the extent of αS in the brain. There was a significant negative association between the observation of Alzheimer’s type II astrocytes and αS pathology in the brain. No association was noted between LP and hyperphosphorylated τ (HPτ). No significant correlation could be seen between the extent of LP and the extent of HPτ, amyloid β protein (Aβ) or transactive DNA binding protein 43 (TDP43) in the brain. There were significant correlations observed between the extent of HPτ, Aβ, αS, and TDP43 in the brain and between liver steatosis, inflammation, and fibrosis. Subjects with severe LP displayed a higher frequency of Alzheimer’s type II astrocytes compared to those with no, or mild, LP. The assessed protein alterations were not more prevalent or severe in subjects with Alzheimer’s type II astrocytes in the brain. In all cases, dementia was attributed to a combination of altered proteins, i.e., mixed dementia and dementia was observed in 30% of those with mild LP when compared with 13% of those with severe LP. In summary, our results are in line with the outcome obtained by the two recent meta-analyses suggesting that subjects with a history of alcohol consumption seldom develop an α-synucleinopathy.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1007/s00401-024-02762-6
Jonasz J. Weber, Leah Czisch, Priscila Pereira Sena, Florian Fath, Chrisovalantou Huridou, Natasa Schwarz, Rana D. Incebacak Eltemur, Anna Würth, Daniel Weishäupl, Miriam Döcker, Gunnar Blumenstock, Sandra Martins, Jorge Sequeiros, Guy A. Rouleau, Laura Bannach Jardim, Maria-Luiza Saraiva-Pereira, Marcondes C. França Jr., Carlos R. Gordon, Roy Zaltzman, Mario R. Cornejo-Olivas, Bart P. C. van de Warrenburg, Alexandra Durr, Alexis Brice, Peter Bauer, Thomas Klockgether, Ludger Schöls, Olaf Riess, The EUROSCA Network, Thorsten Schmidt
Machado–Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia caused by a polyglutamine-coding CAG repeat expansion in the ATXN3 gene. While the CAG length correlates negatively with the age at onset, it accounts for approximately 50% of its variability only. Despite larger efforts in identifying contributing genetic factors, candidate genes with a robust and plausible impact on the molecular pathogenesis of MJD are scarce. Therefore, we analysed missense single nucleotide polymorphism variants in the PRKN gene encoding the Parkinson's disease-associated E3 ubiquitin ligase parkin, which is a well-described interaction partner of the MJD protein ataxin-3, a deubiquitinase. By performing a correlation analysis in the to-date largest MJD cohort of more than 900 individuals, we identified the V380L variant as a relevant factor, decreasing the age at onset by 3 years in homozygous carriers. Functional analysis in an MJD cell model demonstrated that parkin V380L did not modulate soluble or aggregate levels of ataxin-3 but reduced the interaction of the two proteins. Moreover, the presence of parkin V380L interfered with the execution of mitophagy—the autophagic removal of surplus or damaged mitochondria—thereby compromising cell viability. In summary, we identified the V380L variant in parkin as a genetic modifier of MJD, with negative repercussions on its molecular pathogenesis and disease age at onset.
{"title":"The parkin V380L variant is a genetic modifier of Machado–Joseph disease with impact on mitophagy","authors":"Jonasz J. Weber, Leah Czisch, Priscila Pereira Sena, Florian Fath, Chrisovalantou Huridou, Natasa Schwarz, Rana D. Incebacak Eltemur, Anna Würth, Daniel Weishäupl, Miriam Döcker, Gunnar Blumenstock, Sandra Martins, Jorge Sequeiros, Guy A. Rouleau, Laura Bannach Jardim, Maria-Luiza Saraiva-Pereira, Marcondes C. França Jr., Carlos R. Gordon, Roy Zaltzman, Mario R. Cornejo-Olivas, Bart P. C. van de Warrenburg, Alexandra Durr, Alexis Brice, Peter Bauer, Thomas Klockgether, Ludger Schöls, Olaf Riess, The EUROSCA Network, Thorsten Schmidt","doi":"10.1007/s00401-024-02762-6","DOIUrl":"10.1007/s00401-024-02762-6","url":null,"abstract":"<div><p>Machado–Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia caused by a polyglutamine-coding CAG repeat expansion in the <i>ATXN3</i> gene. While the CAG length correlates negatively with the age at onset, it accounts for approximately 50% of its variability only. Despite larger efforts in identifying contributing genetic factors, candidate genes with a robust and plausible impact on the molecular pathogenesis of MJD are scarce. Therefore, we analysed missense single nucleotide polymorphism variants in the <i>PRKN</i> gene encoding the Parkinson's disease-associated E3 ubiquitin ligase parkin, which is a well-described interaction partner of the MJD protein ataxin-3, a deubiquitinase. By performing a correlation analysis in the to-date largest MJD cohort of more than 900 individuals, we identified the V380L variant as a relevant factor, decreasing the age at onset by 3 years in homozygous carriers. Functional analysis in an MJD cell model demonstrated that parkin V380L did not modulate soluble or aggregate levels of ataxin-3 but reduced the interaction of the two proteins. Moreover, the presence of parkin V380L interfered with the execution of mitophagy—the autophagic removal of surplus or damaged mitochondria—thereby compromising cell viability. In summary, we identified the V380L variant in parkin as a genetic modifier of MJD, with negative repercussions on its molecular pathogenesis and disease age at onset.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1007/s00401-024-02773-3
L. P. Priesterbach-Ackley, F. Cordier, P. de Witt Hamer, T. J. Snijders, P. A. Robe, B. Küsters, W. W. J. de Leng, W. F. A. den Dunnen, D. Brandsma, C. Jansen, P. Wesseling, A. Muhlebner
{"title":"Diffuse, IDH-wildtype gliomas in adults with minimal histological change and isolated TERT promoter mutation: not simply CNS WHO grade 4","authors":"L. P. Priesterbach-Ackley, F. Cordier, P. de Witt Hamer, T. J. Snijders, P. A. Robe, B. Küsters, W. W. J. de Leng, W. F. A. den Dunnen, D. Brandsma, C. Jansen, P. Wesseling, A. Muhlebner","doi":"10.1007/s00401-024-02773-3","DOIUrl":"10.1007/s00401-024-02773-3","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}